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Open Access Publications from the University of California

Development of a Phage Display System for Engineering Peptide Inhibitors Containing Multiple Non-Canonical Amino Acids

  • Author(s): Truong, Tan Minh
  • Advisor(s): Ai, Huiwang
  • et al.

Phage display is a powerful screening method capable of potentially screening over 1011 unique peptide sequences for protein-protein or protein-DNA interactions. It has been extensively utilized in manufacturing, basic research, and therapeutics. With the recent creation of a genomically recoded organism, wherein all amber codons were replaced with ochre codons in the C321ΔA E. coli strain, this allows for an expansion the genetic code by reassigning the amber codon to designate a genetic incorporation of synthetic, non-canonical amino acid (ncAA) and opens an exciting avenue for further developing the phage display technology. My aims are to therefore: (1) develop and optimize a phage display system that can efficiently genetically encode multiple, different ncAAs, and subsequently demonstrate this application in a screen for (2) peptide inhibitors to Protein Tyrosine Phosphatase non-receptor type 1 (PTP1B), as well as (3) Src Homology 2 (SH2) domain. PTP1B is implicated in breast cancer, diabetes mellitus type 2, and obesity; and several mutant SH2 domains mediating aberrant protein-protein interactions have been implicated in human diseases, such as congenital heart disease, X-linked agammaglobulinemia and lymphoproliferative syndrome. Developing this technology will enable phage display to become an even more powerful screening method with its new, expanded chemistry set conferred from synthetic ncAAs.

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